Identifying Candida albicans Gene Networks Involved in Pathogenicity

Abstract

Candida albicans is a normal member of the human microbiome. It is also an opportunistic pathogen, which can cause life-threatening systemic infections in severely immunocompromized individuals. Despite the availability of antifungal drugs, mortality rates of systemic infections are high and new drugs are needed to overcome therapeutic challenges including the emergence of drug resistance. Targeting known disease pathways has been suggested as a promising avenue for the development of new antifungals. However, <30% of C. albicans genes are verified with experimental evidence of a gene product, and the full complement of genes involved in important disease processes is currently unknown. Tools to predict the function of partially or uncharacterized genes and generate testable hypotheses will, therefore, help to identify potential targets for new antifungal development. Here, we employ a network-extracted ontology to leverage publicly available transcriptomics data and identify potential candidate genes involved in disease processes. A subset of these genes has been phenotypically screened using available deletion strains and we present preliminary data that one candidate, PEP8, is involved in hyphal development and immune evasion. This work demonstrates the utility of network-extracted ontologies in predicting gene function to generate testable hypotheses that can be applied to pathogenic systems. This could represent a novel first step to identifying targets for new antifungal therapies.

PHI-base in 2022: a multi-species phenotype database for Pathogen–Host Interactions

“…These methods were used by three recent studies that specifically took the high-level phenotype annotations assigned to PHI-base proteins to construct networks of rice-pathogen interactions ( 54 ), to identify and build annotated networks for putative virulence factors for 14 Ascomycete fungal pathogens ( 55 ), and to generate ontologies, extracted from an interaction network, that led to the identification of the PEP8 protein in the human infecting fungal pathogen Candida albicans . PEP8 is likely involved in retrograde vesicle transport, with a function in hyphal development and immune evasion ( 56 ).…”

“…These will be stored in a new resource to be available on the gene pages (both for hosts and pathogens) and via direct downloads of the data. Given the wide representation of species within Ensembl (vertebrates to metazoa to plants) ( 56 ), this will provide a platform that can capture relationships between any two proteins from any two species, thus greatly expanding the potential scope of this resource to many fields of study, such as agriculture, human and animal health, and ecology.…”

Coexpression network analysis of human candida infection reveals key modules and hub genes responsible for host-pathogen interactions

“…Recent efforts have been made for the functional and molecular characterization of C. albicans genes using RNA sequencing ( Wu et al, 2016 ; Brown et al, 2019 ; Romo et al, 2019 ; Zhang et al, 2019 ; de Vries et al, 2020 ; Thomas et al, 2020 ; Xu et al, 2020 ). Numerous studies suggest gene biomarkers as potential therapeutic targets and diagnostic markers in various fungal infections ( Dix et al, 2015 ; Huppler et al, 2017 ; Díez et al, 2021 ; Hamam et al, 2021 ).…”

“…Numerous studies suggest gene biomarkers as potential therapeutic targets and diagnostic markers in various fungal infections ( Dix et al, 2015 ; Huppler et al, 2017 ; Díez et al, 2021 ; Hamam et al, 2021 ). Weighted gene correlation network analysis (WGCNA) has been widely used in disease diagnosis ( Liu et al, 2017 ; Liang et al, 2018 ; Tang et al, 2018 ; Li et al, 2019 ; Yin et al, 2019 ), physiology ( Kadarmideen et al, 2011 ; Zuo et al, 2018 ; Chen et al, 2019 ), drug targets ( Puniya et al, 2013 ; Maertens et al, 2018 ), and cross-species ( Mueller et al, 2017 ) but has never been applied in the context of candida pathogenesis ( Thomas et al, 2020 ). Therefore, we developed a novel approach to identify host-pathogen interactions in C. albicans and humans.…”

Revealing the astragalin mode of anticandidal action

“…Upon attachment to the host cells, a characteristic feature of C. albicans is the ability to switch from avirulent yeast form of growth to invasive hyphal form. This pathogenic transition is accompanied by increased levels of reactive oxygen species (ROS) and expression of several hyphal specific genes and proteins (Schröter et al, 2000[ 19 ]; Thomas et al, 2020[ 28 ]). Several drugs are currently in use to combat candidiasis, but Candida spp are able to modify their response to antifungals to be able to survive the treatment.…”